Long chain aliphatic alcohol derivatives and methods of making and using same

ABSTRACT

This application pertains to compounds comprising unbranched long chain aliphatic alcohols linked to a heterocyclic carboxylic acid moiety by means of an ester or ether linkage. The aliphatic alcohols may include aliphatic alcohols present in polycosanol, such as octacosanol. The heterocyclic carboxylic acid moieties include a 5-membered ring, a 6-membered ring, or a bicyclic ring. In one embodiment, the compounds of the invention include 1-octacosanyl nicotinate and salts thereof. The invention includes prodrugs, pharmaceutically acceptable salts, and pharmaceutical compositions of the compounds, and methods of making and using the compounds.

BACKGROUND

Polycosanol is a mixture of long chain alcohols that can be isolated from a number of plants, including sugar cane. Polycosanol has been found to reduce blood cholesterol levels by reducing levels of low-density lipoproteins (LDLs), which are associated with an increase in the risk of cardiovascular disease. Polycosanol also raises levels of high-density lipoproteins (HDLs), which are associated with a decrease in the risk of cardiovascular disease. Further, polycosanol has also been found to prevent the formation of arterial wall lesions, and to act as an anti-coagulant (Varada et al., Nutr. Rev. November 2003: 61(11):375-83) and prevent platelet aggregation (Taylor et al., Nutrition, Vol. 19, 192-195, 2003). Preventing platelet aggregation and blood coagulation may help reduce incidences of stroke and blood clotting. Polycosanol may also enhance athletic performance and may inhibit stomach ulcer formation aggregation (Taylor et al., Nutrition, Vol. 19, 192-195, 2003).

One of the main components of polycosanol is the long chain aliphatic alcohol octacosanol. Other aliphatic alcohols, which may be present in polycosanol include hexacosanol, triacontanol, eicosanol, tetracosanol, nonacosanol, dotriacontanol, tetratriacontanol, and heptacosanol.

Nicotinic acid, also known as niacin, is a water-soluble B vitamin. Nicotinic acid is a heterocyclic carboxylic acid. Nicotinic acid can also lower LDL levels and raise HDL levels. In addition, nicotinic acid lowers triglyceride levels, which can also help reduce the risk of heart disease. However, serious side effects are associated with the use of nicotinic acid including hot flushes, gastrointestinal disorders, hepatotixicity, gout, and blood sugar level elevation (www.nhlbi.nih.gov/chd/meds3.htm; Am. J. Health Syst Pharm. Jul. 1, 2003; 60(13 Suppl 2):S9-14).

Many aliphatic alcohol derivatives are described in the prior art. For example, Bertelsen et al. have described structural elucidation of alkyl-branched chain aliphatic alcohols by mass spectrometry of their respective alkyl nicotinate and picolinyl carboxylate derivatives.¹ The Bertelsen et al. paper describes transformation of aliphatic alcohols into alkyl nicotinates by condensation with nicotinyl chloride hydrochloride. All of the esters obtained were alkyl-branched chain alkyl nicotinates. No unbranched chain alkyl nicotinates were characterized. Moreover, Bertelsen et al. did not describe possible use of the esters for reducing risk of cardiovascular disease, such as by lowering serum cholesterol levels. ¹Bertelsen et al. Structural Elucidation of Alkyl-Branched Chain Aliphatic Alcohols and Fatty Acids by Mass Spectrometry of their Respective Alkyl Nicotinate and Picolinyl Carboxylate Derivatives, Fette, Seifen, Anstrichmittel (1985), 87(9), 336-42

There is a need for new aliphatic alcohol derivatives having the beneficial effects of polycosanol and nicotinic acid.

SUMMARY OF INVENTION

The invention pertains to compounds comprising aliphatic alcohols linked to heterocyclic carboxylic acid moieties. The linkages can be ester or ether linkages. The aliphatic alcohols may include alcohols comprising polycosanol, such as octacosanol.

The aliphatic alcohols can comprise unbranched aliphatic alcohols having 20 to 34 carbons, such as aliphatic alcohols derived from polycosanol. Such alcohols include octacosanol, hexacosanol, triacontanol, eicosanol, tetracosanol, nonacosanol, dotriacontanol, tetratriacontanol, and heptacosanol.

The heterocyclic carboxylic acid moieties include a 5-membered ring, a 6-membered ring, or a bicyclic ring. The bicyclic ring can comprise 5-membered rings, 6-membered rings, or both. The ring may include a nitrogen atom. In some embodiments, the heterocyclic carboxylic acid moiety is nicotinic acid. In one embodiment, the compounds include 1-octacosanyl nicotinate and salts thereof

The invention also includes prodrugs of the compounds, pharmaceutically acceptable salts of the compounds, and pharmaceutical compositions comprising the compounds of the invention, pharmaceutically acceptable salts of the compounds, and prodrugs of the compounds.

The invention also pertains to methods of making the compounds and methods of reducing blood cholesterol levels and blood triglyceride levels, methods of preventing the formation of arterial wall lesions, methods of preventing platelet aggregation, methods of enhancing athletic performance, methods of inhibiting stomach ulcer formation, and methods of treating any condition responsive to polycosanol or nicotinic acid therapy.

DESCRIPTION

Throughout the following description, specific details are set forth in order to provide a more thorough understanding of the invention. However, the invention may be practiced without these particulars. In other instances, well known elements have not been shown or described in detail to avoid unnecessarily obscuring the invention. Accordingly, the specification and drawings are to be regarded in an illustrative, rather than a restrictive, sense.

This invention pertains to aliphatic alcohol derivatives and methods of making and using same. The compounds of the invention comprise aliphatic alcohols linked to a heterocyclic carboxylic acid moiety by means of an ester or ether linkage.

The aliphatic alcohols can comprise any unbranched aliphatic alcohol, such as an aliphatic alcohol found in polycosanol. In some embodiments the aliphatic alcohols have between 20 and 34 carbons and include octacosanol, hexacosanol, triacontanol, eicosanol, tetracosanol, nonacosanol, dotriacontanol, tetratriacontanol, and heptacosanol. In one embodiment, the aliphatic alcohol comprises octacosanol.

The heterocyclic carboxylic acid moieties can comprise a 5-membered heterocyclic ring, a 6-membered heterocyclic ring, or a bicyclic heterocyclic ring. The bicyclic ring can comprise either two 5-membered rings, two 6-membered rings, or one 5-membered ring and one 6-membered ring. The heterocyclic ring of the heterocyclic carboxylic acid moieties may also comprise a nitrogen atom. The heterocyclic carboxylic acid moieties can be derived from nicotinic acid, indole carboxylic acid, dihydroindole carboxylic acid, quinoline carboxylic acid, dihydroquinoline carboxylic acid, tetrahydroquinoline carboxylic acid, isoquinoline carboxylic acid, pyridine carboxylic acid, piperidine carboxylic acid, methylindole carboxylic acid, methyldihydroindole carboxylic acid, methylquinoline carboxylic acid, methyldihydroquinoline carboxylic acid, methyltetrahydroquinoline carboxylic acid, methylisoquinoline carboxylic acid, pyrrolidine carboxylic acid, furan carboxylic acid, tetrahydrofuran carboxylic acid, benzofuran carboxylic acid, thiophene carboxylic acid, tetrahydrothiophene carboxylic acid, benzothiophene carboxylic acid, methylbenzothiophene carboxylic acid, methylpyridine carboxylic acid, methylpiperidine carboxylic acid, methylpyrrolidine carboxylic acid, methylfuran carboxylic acid, methyltetrahydrofuran carboxylic acid, methylbenzofuran carboxylic acid, methylthiophene carboxylic acid, methyltetrahydrothiophene carboxylic acid, and dimethylbenzothiophene carboxylic acid. In one embodiment, the heterocyclic carboxylic acid moiety is derived from nicotinic acid.

The aliphatic alcohol and the heterocyclic carboxylic acid moiety can be linked through ester or ether linkages. In one embodiment, the compound of the invention is the ester octacosanyl nicotinate having the formula:

In other embodiments, the compounds of the invention have the following formulae:

The invention also includes pharmaceutically acceptable salts of the above compounds. Such salts include hydrochlorides, chlorides, fluorides, phosphates, sulphates, acetates, nitrates, and other acceptable salts.

The invention also pertains to prodrugs transformable into the compounds of the invention. Such prodrugs include salts of the compounds of the invention. In one embodiment, the salt is a chloride salt.

The invention also pertains to pharmaceutical compositions comprising the compounds of the invention, pharmaceutically acceptable salts of the compounds, and prodrugs transformable into the compounds. The pharmaceutical compositions comprise a pharmaceutically effective amount of one or more of the compounds, salts of the compounds or prodrugs of the compounds and a pharmaceutically effective carrier.

The invention also pertains to methods of reducing blood cholesterol levels and blood triglyceride levels, methods of preventing the formation of arterial wall lesions, methods of preventing platelet aggregation, methods of enhancing athletic performance, methods of inhibiting stomach ulcer formation, and methods of treating any condition responsive to polycosanol or nicotinic acid therapy using the compounds of the invention, pharmaceutically acceptable salts of the compounds, prodrugs of the compounds, or pharmaceutical compositions containing the compounds, pharmaceutically acceptable salts of the compounds, or prodrugs of the compounds. The compounds of the invention can be used to treat any condition responsive to treatment with polycosanol or nicotinic acid by administering the compounds of the invention, the salts of the compounds, the prodrugs of the compounds, or any pharmaceutical composition containing the compounds, salts of the compounds, or prodrugs of the compounds and a pharmaceutically acceptable carrier to a patient in need of treatment.

The invention also pertains to methods of making the compounds of the invention. In one embodiment, the method includes steps for producing octocosanol and for producing the compound of the invention in the form of an ester.

The method for producing octacosanol comprises:

-   -   a) Extracting wax from plants using ethanol;     -   b) Saponifying and hydrolyzing the wax using Ca(OH)₂, KOH, NaOH,         or any other suitable base;     -   c) Filtering away insoluble precipitate;     -   d) Cooling the filtrate to 5° C. to −20° C. for 24 hours or more         to produce a mixture of long chain fatty alcohols;     -   e) Vacuum distilling the residual alcohol mixture to separate         individual alcohols;     -   f) Optionally repeating the vacuum distilling step;     -   g) Recrystalizing octacosanol from the separate individual         alcohols; and     -   h) Oven drying octacosanol to remove residual solvent.         In one embodiment of the invention, the wax is saponified with         Ca(OH)₂ and the filtrate is cooled to 0° C. to 5° C.

The method of producing the compound of the invention comprises:

-   -   a) converting a heterocyclic carboxylic acid into a salt; and     -   b) reacting the salt of the heterocyclic carboxylic acid with an         aliphatic alcohol.

In one embodiment of the invention, the method comprises steps for making 1-octacosanyl nicotinate and salts thereof, said method comprising:

-   -   a) conversion of nicotinic acid to nicotinyl chloride using         thionyl chloride or phosphorus oxychloride; and     -   b) reaction of nicotinyl chloride with octacosanol to yield         1-octacosanyl nicotinate hydrochloride.         The reaction can take place in the presence of solvents such as         ethers, including diethyl ether, tetrahydrofuran, and dioxane,         or in the presence of chlorinated solvents, including         chloroform, dichloromethane, and carbon tetrachloride, or any         other suitable solvent.

The salt 1-octacosanyl nicotinate hydrochloride can be further reacted with NaHCO₃ to obtain octacosanyl nicotinate ester.

In a further option, 1-octacosanyl nicotinate hydrochloride can be obtained from octacosanyl nicotinate ester by reacting octacosanyl nicotinate ester with HCl to obtain octacosanyl nicotinate hydrochloride (see Scheme 1).

EXAMPLES

The following examples illustrate embodiments of the invention and are not intended to limit the scope of the invention.

1. Octacosanol Extraction Method

Wax extract can be produced from sugarcane wax or other plant materials. Extraction was carried out by extracting of 100 kg sugarcane wax with 500 L of food grade ethanol. Saponification and hydrolysis was achieved using 10% Ca(OH)₂ solution at 60-100° C. for 2-10 hours. The insoluble precipitate was filtered off and the filtrate was cooled at 0-5° C. for 24 hours to produce a mixture of long chain fatty alcohols. The residual alcohol mixture was vacuum distilled at 180-250° C. to separate the individual alcohols. The distillation procedure was repeated to obtain 95% pure C28 alcohol (Octacosanol). The product was recrystalized twice to increase the purity to more than 98% and oven dried to remove the residual solvent. The analytical results have illustrated the following long chain fatty alcohol compositions:

C24 Alcohol 0-1.0%

C26 Alcohol 0.5-2.0%

C27 Alcohol 0.3-1.0%

C28 Alcohol 90-98% or greater

C29 Alcohol 0.3-1.0%

C30 Alcohol 0.6-4%

C32 Alcohol 0.3-1.0%

2. Synthesis of 1-octacosanyl nicotinate hydrochloride

Commercial SOCl₂ (>99.5) and nicotinic acid (>99.5) were used without any further purification. To a three-necked flask was added nicotinic acid (16.9 g, 0.137 mol) under dry nitrogen atmosphere, and commercial SOCl₂ (50 ml, 0.685 mol) was added dropwise. The mixture was heated to reflux for 3 hours and SOCl₂ was evaporated under dry nitrogen atmosphere. After cooling to room temperature, 1-octacosanol (23.45 g, 0.057 mol) and CHCl₃ (300 ml, dried anhydrous Na₂SO₄) were added to the nicotinic chloride and the mixture was heated to reflux for 4 hours. After cooling to room temperature overnight, the mixture was filtered under reduced pressure. The precipitate was dissolved in warm CHCl₃ (800 ml) and then saturated NaHCO₃ (100 ml) was added slowly. After stirring at room temperature for 1 hour, the organic layer was separated, washed with deionized water, brine and then dried over anhydrous Na₂SO₄. After the removal of the organic solvent, the residue was dissolved in warm CHCl₃ (150 ml) and concentrated HCl (5 ml) was added with vigorous stirring for 30 minutes. The mixture was filtered under reduced pressure and the precipitate was washed with deoinized water, 95% EtOH, to obtain the product octacosanyl nicotinate hydrochloride (28.4 g, 90.3% yield, mp: 58-60° C.) as a pale yellow solid, and then re-crystallized with CHCl₃ to give 24.3 g of octacosanyl nicotinate hydrochloride in yield 77.3%, mp: 74-75° C.

3. Synthesis of 1-octacosanyl nicotinate

To a solution of 1-octacosanyl nicotinate hydrochloride in warm CHCl₃ was added saturated NaHCO₃ slowly. The aqueous layer was kept basic and the mixture was stirred for 1 hour at room temperature. The organic layer was then separated, washed with deionized water, brine and dried over anhydrous Na₂SO₄. After the removal of the organic solvent, the residue was crystallized with CHCl₃ to give 1-octacosanyl nicotinate as a pale yellow waxy solid, mp: 65-70° C.

4. Spectroscopic Analysis

¹H spectra were recorded in CDCl₃ on a VARIAN MERCURY-300. The LCMS data were recorded using a Waters ZQ10 instrument. The purification of the final products (1-octacosanyl nicotinate and 1-octacosanol nicotinate hydrochloride) were all 100.0 detected by HPLC on a HP1100 instrument.

1-Octacosanyl nicotinate hydrochloride

¹HNMR(CDCL₃, 300 MHz): 0.87(3H,t,J=6 Hz,—CH3), 1.24-1.80(52H,m,—(CH2)26-), 4.35(2H, t, J=6.6 Hz, —OCH2-), 7.26(solvent), 7.39(¹H,dd, J1=4.2, J2=7.8, Ar—H5), 8.30(¹H, d, J=7.8, Ar—H4), 8.77(¹H, d, J=4.2, Ar—H6), 9.23(¹H, s, Ar—H2). EI-MS:515(85,M+), 486(10,M-29), 124(100).

LCMS of 1-octacosanyl nicotinate ester

Solvent: tetrahydrofuran—water=9:1.

Ionization—positive

Calculated mass for molecular ion [M.H]+(C34H62NO2)=516.478055

Determined mass=517.09

LCMS of octacosanoyl nicotinate hydrochloride

Solvent: tetrahydrofuran—water=9:1.

Ionization—negative

Calculated mass for molecular ion [M-H]—(C34H61ClNO2)=550.439083.

Determined mass=551.05.

As will be apparent to those skilled in the art in the light of the foregoing disclosure, many alterations and modifications are possible in the practice of this invention without departing from the spirit or scope thereof. Accordingly, the scope of the invention is to be construed in accordance with the substance defined by the following claims. 

1. A compound selected from the group consisting of compounds represented by formula (I) and formula (II),

wherein said n is 19 to 33, and wherein R is a heterocyclic ring moiety; and stereoisomers and pharmaceutically acceptable salts thereof.
 2. A compound according to claim 1, wherein n is
 27. 3. A compound according to claim 1, wherein the heterocyclic ring moiety is selected from a group consisting of a 5-membered ring, a 6-membered ring, and a bicyclic ring, wherein the bicyclic ring comprises 5-membered rings, 6-membered rings, or both.
 4. A compound according to claim 3, wherein the heterocyclic ring moiety comprises N.
 5. A compound according to claim 1, wherein R is selected from the group consisting of a nicotinyl, indole carboxyl, dihydroindole carboxyl, quinoline carboxyl, dihydroquinoline carboxyl, tetrahydroquinoline carboxyl, isoquinoline carboxyl, pyridine carboxyl, piperidine carboxyl, methylindole carboxyl, methyldihydroindole carboxyl, methylquinoline carboxyl, methyldihydroquinoline carboxyl, methyltetrahydroquinoline carboxyl, methylisoquinoline carboxyl, pyrrolidine carboxyl, furan carboxyl, tetrahydrofuran carboxyl, benzofuran carboxyl, thiophene carboxyl, tetrahydrothiophene carboxyl, benzothiophene carboxyl, methylbenzothiophene carboxyl, methylpyridine carboxyl, methylpiperidine carboxyl, methylpyrrolidine carboxyl, methylfuran carboxyl, methyltetrahydrofuran carboxyl, methylbenzofuran carboxyl, methylthiophene carboxyl, methyltetrahydrothiophene carboxyl, methylbenzothiophene carboxyl, and dimethylbenzothiophene carboxyl group.
 6. A compound according to claim 1, wherein R is a nicotinyl group.
 7. A compound according to claim 1, wherein said compound is selected from the group consisting of octacosanyl nicotinate, octacosanyl indole carboxylate, octacosanyl dihydroindole carboxylate, octacosanyl quinoline carboxylate, octacosanyl dihydroquinoline carboxylate, octacosanyl tetrahydroquinoline carboxylate, octacosanyl isoquinoline carboxylate, octacosanyl pyridine carboxylate, octacosanyl piperidine carboxylate, octacosanoxymethylindole, octacosanoxymethyldihydroindole, octacosanoxymethylquinoline, octacosanoxymethyldihydroquinoline, octacosanoxymethyltetrahydroquinoline, octacosanoxymethylisoquinoline, octacosanyl pyrrolidine carboxylate, octacosanol furan carboxylate, octacosanyl tetrahydrofuran carboxylate, octacosanyl benzofuran carboxylate, octacosanyl thiophene carboxylate, octacosanyl tetrahydrothiophene carboxylate, octacosanyl benzothiophene carboxylate, 2-octacosanyl-3-methylbenzothiophene carboxylate, 3-octacosanyl-2-methylbenzothiophene carboxylate octacosanoxymethylpyridine, octacosanoxymethylpiperidine, octacosanoxymethylpyrrolidine, octacosanoxymethylfuran, octacosanoxymethyltetrahydrofuran, octacosanoxymethylbenzofuran, octacosanoxymethylthiophene, octacosanoxymethyltetrahydrothiophene, octacosanoxymethylbenzothiophene, 2-methyloctacosanoxy-3-methylbenzothiophene, and 3-methyloctacosanoxy-2-methylbenzothiophene.
 8. A compound according to claim 1, wherein the compound is 1-octacosanyl nicotinate.
 9. A prodrug transformable in vivo to a compound according to claim
 1. 10. A prodrug according to claim 9, comprising a salt of said compound.
 11. A pro drug according to claim 10, comprising a HCl salt of said compound.
 12. A pharmaceutical composition comprising an effective amount of one or more compounds according to claim 1 together with one or more pharmaceutically acceptable carriers.
 13. A pharmaceutical composition comprising an effective amount of one or more prodrugs according to claim 9 together with one or more pharmaceutically acceptable carriers.
 14. A method of reducing blood cholesterol levels, or reducing blood triglyceride levels, or preventing the formation of arterial wall lesions, or preventing platelet aggregation, or enhancing athletic performance, or inhibiting stomach ulcer formation, or treating any other condition responsive to polycosanol or nicotinic acid therapy comprising administering a therapeutically effective amount of a compound according to claim
 1. 15. A method of reducing blood cholesterol levels, or reducing blood triglyceride levels, or preventing the formation of arterial wall lesions, or preventing platelet aggregation, or enhancing athletic performance, or inhibiting stomach ulcer formation, or treating any other condition responsive to polycosanol or nicotinic acid therapy comprising administering a therapeutically effective amount of a compound according to claim
 8. 16. A method of reducing blood cholesterol levels, or reducing blood triglyceride levels, or preventing the formation of arterial wall lesions, or preventing platelet aggregation, or enhancing athletic performance, or inhibiting stomach ulcer formation, or treating any other condition responsive to polycosanol or nicotinic acid therapy comprising administering a therapeutically effective amount of a prodrug according to claim
 9. 17. A method of reducing blood cholesterol levels, or reducing blood triglyceride levels, or preventing the formation of arterial wall lesions, or preventing platelet aggregation, or enhancing athletic performance, or inhibiting stomach ulcer formation, or treating any other condition responsive to polycosanol or nicotinic acid therapy comprising administering a therapeutically effective amount of a pharmaceutical composition according to claim
 12. 18. A method of reducing blood cholesterol levels, or reducing blood triglyceride levels, or preventing the formation of arterial wall lesions, or preventing platelet aggregation, or enhancing athletic performance, or inhibiting stomach ulcer formation, or treating any other condition responsive to polycosanol or nicotinic acid therapy comprising administering a therapeutically effective amount of a pharmaceutical composition according to claim
 13. 19. A method of synthesizing a compound according to claim 1 comprising the steps of converting a heterocyclic carboxylic acid into a salt, and reacting the salt of the heterocyclic carboxylic acid with an aliphatic alcohol having between 20 and 34 carbons.
 20. A method of synthesizing a compound according to claim 8 comprising the steps of: a) Converting nicotinic acid to nicotinyl chloride using thionyl chloride or phosphorus oxychloride; b) Reacting nicotinyl chloride with octacosanol to produce 1-octacosanyl nicotinate hydrochloride; and c) Reacting 1-octacosanyl nicotinate hydrochloride with NaHCO₃ to obtain octacosanyl nicotinate.
 21. A method of synthesizing a salt of the compound according to claim 8 comprising the steps of: a) Converting nicotinic acid to nicotinyl chloride using thionyl chloride or phosphorus oxychloride; and b) Reacting nicotinyl chloride with octacosanol to produce 1-octacosanyl nicotinate hydrochloride.
 22. A method of synthesizing a salt of the compound according to claim 8 comprising the steps of reacting octacosanyl nicotinate with HCl to obtain octacosanyl nicotinate hydrochloride.
 23. A method of obtaining octacosanol at a purity of 98% or greater according to the following steps: a) Extracting wax from plants using ethanol; b) Saponifying and hydrolyzing the wax using a base selected from the group consisting of Ca(OH)₂ , NaOH, and KOH; c) Filtering away insoluble precipitate; d) Cooling the filtrate to 5° C. to −20° C. for 24 hours to produce a mixture of long chain fatty alcohols; e) Vacuum distilling the residual alcohol mixture to separate individual alcohols; f) Optionally repeating the vacuum distilling step; g) Recrystalizing octacosanol from the separate individual alcohols; and h) Oven drying octacosanol to remove residual solvent.
 24. A method according to claim 23, wherein the plant is sugar cane.
 25. A method according to claim 23, wherein filtrate is cooled to 0° C. to 5° C.
 26. A method according to claim 23, wherein the wax is saponified with Ca(OH)₂.
 27. A compound according to claim 1, wherein the carbon chain

is unbranched.
 28. A compound selected from the group consisting of compounds represented by formula (I) and formula (II)

wherein said n is 19 to 33, and wherein R is a heterocyclic ring moiety; and stereoisomers and pharmaceutically acceptable salts thereof. 